High Thymic Output of Effector CD4+ Cells May Lead to a Treg : T Effector Imbalance in the Periphery in NOD Mice.
High Thymic Output of Effector CD4+ Cells May Lead to a Treg : T Effector Imbalance in the Periphery in NOD Mice.
复制标题
效应器 CD4 细胞的高胸腺输出可能导致 NOD 小鼠外周 Treg-:-T 效应器不平衡。
DOI：
10.1155/2019/8785263
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发表时间：
2019
影响因子：
4.1
通讯作者：
Kosiewicz,MicheleM
中科院分区：
文献类型：
--
作者：
Zhao,Yuan;Alard,Pascale;Kosiewicz,MicheleM
调节性T细胞（Treg）在控制自身反应性T细胞方面发挥着关键作用，Treg的数量和/或质量缺陷与人类和小鼠的自身免疫性疾病（包括1型糖尿病（T1 D））相关。NOD小鼠中T1D的发病率和外周T1D的百分比在动物设施之间差异很大。在我们的动物设施中，NOD小鼠中T1D的发生率高达90 - 100%，并且在首次检测到高葡萄糖之前不久（约12周），约9 - 10周龄雌性NOD小鼠的外周CD4 + Foxp3+细胞百分比与对照（B6）小鼠相比有所降低。这些数据表明，在这个年龄段，T细胞和潜在致病性效应T细胞之间存在不平衡，这可能对疾病进展为显性糖尿病产生重大影响。本研究的目的是研究在NOD小鼠外周Treg：T效应细胞平衡中发挥作用的机制，包括持续/存活、外周稳态增殖和胸腺产生和CD4 + T细胞输出的差异。我们发现NOD和B6小鼠之间的持续性/存活或稳态增殖的TcR或效应T细胞没有差异。此外，尽管与B6小鼠相比，NOD小鼠胸腺中CD4 + Foxp3+细胞的百分比和绝对数量未降低，但9周龄NOD小鼠中Foxp3+的CD4+近期胸腺移出物（RTE）的百分比显著较低。有趣的是，与B6小鼠相比，NOD小鼠中CD4 + Foxp3+细胞的胸腺输出并不低，而NOD小鼠中CD4 + Foxp3-细胞的胸腺输出显著较高。这些数据表明，CD4 + Foxp3-T细胞的较高胸腺输出至少部分地导致NOD小鼠外周CD4 + Foxp3 + T细胞百分比较低，以及T细胞和T效应细胞之间的失衡，这可能导致全面糖尿病的发展。
Regulatory T cells (Tregs) play a critical role in controlling autoreactive T cells, and quantitative and/or qualitative deficiencies in Tregs are associated with autoimmune diseases, including type 1 diabetes (T1D), in both humans and mice. Both the incidence of T1D and percentages of peripheral Tregs in NOD mice vary considerably between animal facilities. In our animal facility, the incidence of T1D in NOD mice is high at 90‐100% and the percentages of peripheral CD4+Foxp3+cells in ~9‐10‐week‐old female NOD mice are decreased compared to control (B6) mice shortly before high glucose is first detected (~12 weeks). These data suggest that there is an imbalance between Tregs and potentially pathogenic effector T cells at this age that could have significant impact on disease progression to overt diabetes. The goal of the current study was to investigate mechanisms that play a role in peripheral Treg : T effector cell balance in NOD mice, including differences in persistence/survival, peripheral homeostatic proliferation, and thymic production and output of CD4+T cells. We found no differences in persistence/survival or homeostatic proliferation of either Tregs or effector T cells between NOD and B6 mice. Furthermore, although the percentages and absolute numbers of CD4+Foxp3+cells in thymus were not decreased in NOD compared to B6 mice, the percentage of CD4+recent thymic emigrants (RTE) that were Foxp3+was significantly lower in 9‐week‐old NOD mice. Interestingly, the thymic output of CD4+Foxp3+cells was not lower in NOD mice, whereas the thymic output of CD4+Foxp3-cells was significantly higher in NOD mice at that age compared to B6 mice. These data suggest that the higher thymic output of CD4+Foxp3-T cells contributes, at least in part, to the lower percentages of peripheral CD4+Foxp3+Tregs in NOD mice and an imbalance between Tregs and T effector cells that may contribute to the development of full‐blown diabetes.